We have previously shown that I3 PUFA reduced prostate cancer (PCa) growth, slowed histopathological progression and increased survival, whereas I6 PUFA had the opposite effects. To systematically assess the interaction between oxygenases and PUFAs in PCa, we knocked out Cox1, Cox2, Lox5, Lox12, and Lox15 in prostate-specific Pten-null mice. Our results indicate a complex PUFA-gene interaction in PCa: (a) Loss of Cox1 had significant effects on PCa growth in a PUFA-dependent manner; namely, tumor growth was significantly diminished in Cox1 knockout mice on I6 diet, whereas it increased in mice on I3 diet. In other words, Cox1 was required for the protective effects of I3 PUFA, suggesting that I3 metabolites of Cox1 (e.g. PGE3) are involved. On the other hand, I6 metabolites of Cox1 (e.g. PGE2) play a promoting role on tumor formation. (b) Loss of Cox2 reduced PCa growth on both I6 and I3 diet. Therefore, I6 metabolites of Cox2 promote tumor growth, and suppressive effects of I3 PUFA do not depend upon Cox2. (c) Loss of Lox5 reduced PCa growth on I6 diet but had no effect on I3 diet, suggesting that I6 metabolites of Lox5 (e.g. LTB4) promote tumor growth, and protective effects of I3 PUFA are independent of Lox5. (d) Loss of Lox12 or Lox15 did not affect PCa growth, suggesting that these two enzymes are not critical for PCa in our model. We hypothesize that I3 PUFA is primarily metabolized by Cox1 in vivo and that the anti-proliferative effect of I3 PUFA is, in part, mediated by Cox1 metabolite(s). Furthermore, I6 PUFA is metabolized by Cox1, Cox2 and Lox5, and the corresponding metabolites play important roles in stimulating PCa growth. To test our hypothesis, three specific aims are proposed: (1) Study the cellular mechanism(s) of PUFA-gene interaction on PCa growth, (2) Identify metabolite(s) of I3 and I6 PUFA important in PCa and (3) Examine metabolite signaling in PCa cell proliferation and apoptosis.